Method of preparing morpholino cyano-acrylamides

ABSTRACT

A compound   WHERE R&#39;&#39; is hydrogen or lower alkyl, the compound being usable as an intermediate in the preparation of 4-hydroxypyrazolo(3,4d)pyrimidine (Allopurinol) and its useful relatives. A method of preparing   WHICH COMPRISES REACTING R&#39;&#39;C(OR)3, morpholine and cyanoacetamide where R&#39;&#39; is hydrogen or lower alkyl and R is lower alkyl.

United States Patent Cresswell et al.

[ 51 Aug. 8, 1972 [54] METHOD OF PREPARING MORPHOLINO CYANO- ACRYLAMIDES [72] Inventors: Ronald M. Cresswell, Scarsdale; John W. Mentha, Hartsdale; Russell 21 Appl. No.: 781,590

[30] Foreign Application Priority Data Feb. 2, 1968 Great Britain ..5,397/68 [52] US. Cl. ..260/310, 260/2472, 260/8564,

[51] Int. Cl. ..C07d 49/02 [58] Field of Search ..260/3 10C, 310 R, 256.4 F

[56] References Cited UNITED STATES PATENTS 3,408,362 10/1968 Druey et al ..260/310 OTHER PUBLICATIONS Robins, J.A.C.S., v01. 78 (1956) pp. 784- 790 Primary Examiner-Alex Mazel Assistant Examiner-James H. Tumipseed Attorney-Sewall P. Bronstein and Donald Brown [57] ABSTRACT A compound R ooum 6 N -c :=o L

where R is hydrogen or lower alkyl, the compound being usable as an intermediate in the preparation of 4-hydroxypyrazolo[3,4-d]pyrimidine (Allopurinol) and its useful relatives.

A method of preparing R C ONH:

which comprises reacting R'C(OR) morpholine and cyanoacetamide where R is hydrogen or lower alkyl and R is lower alkyl.

2 Claims, No Drawings METHOD OF PREPARING MORPHOLINO CYANO- ACRYLAMIDES This invention is directed to new morpholino cyanoacrylarnide compounds and methods for their preparation, and to methods of preparing useful pyrazolo[3,4- d]pyrimidine derivatives therefrom.

One of the useful compounds which is-prepared according to the methods of this invention is 4 -hydroxypyrazolo[ 3 ,4-d]pyrimidine (I),

also known as Allopurinol, which is useful as an inhibitor of the enzyme Xanthine oxidase, in vivo and which is also useful in the treatment of gout.

Allopurinol is a drug which is normally administered to humans in relatively large doses (i.e. 100-800 mg) per person per day and is generally given over extended periods.

Thus the purity of the product is of extreme importance, more so than with most pharmaceuticals, since undesirable contaminants may have a cumulative detrimental effect if taken over extended periods of time.

Therefor there has developed the need for not only an economical method of preparing Allopurinol, but also a method whereby Allopurinol could be prepared in a satisfactory pure state without the need of using excessive and expensive purification steps.

The methods and compounds of this invention are also useful in the preparation of other useful pyrazolo pyrimidine derivatives reported in the literature, such as 4,6-dihydroxy pyrazolo( 3,4-d)pyrimidine.

A number of methods of synthesis are known for producing Allopurinol (I), for example:

ON ON ROOC H Where R is an alkyl, for example ethyl;

ON ON Method (a) noted above, although providing Allopurinol in good yield, produces a product with considerable colored contaminants which are expensive to remove. These colored contaminants arise, at least in part, because the final ring closure in formamide requires temperatures in excess of 160 C where decomposition is known to occur. This is also an inconvenient temperature for large scale manufacture as it is not readily achieved using super-heated steam. 7

Method (b) noted above is long, costly and the intermediate (II) used in the final step requires recrystallization before it can be used to make satisfactory Allopurinol even though the temperature in the final step is only l-l45 C. In addition the products from the reaction of ethylcyanoacetate and triethylorthoformate and malononitrile and triethylorthoformate in (a) and (b) above cause allergic contact dermatitis and since they need to be isolated because of purity considerations this property creates extreme difficulties in large scale manufacture.

Method (c) noted above provides a superior end product to (a) and (b) and does so in a more economical manner, but even though the 3-amino-2- cyanoacrylamide formed en route can be reacted without isolation the intermediate (11) still requires recrystallization, and the method also requires the preparation of formamidine.

With the methods of the present invention, not only is a superior purity end product (i.e. Allopurinol) obtained, but the process is much more economical than the prior art processes.

In its broadest aspect this invention comprises the method of preparation of novel compounds of the formula(l1l) C ONHa III tormamide o ONH: l l H! D I ON ON Iormamlde I which comprises reacting a compound R'C(OR) where R is lower alkyl (methyl, ethyl, propyl, and butyl) and is preferably ethyl, and R is hydrogen or lower alkyl (methyl, ethyl, propyl, and butyl) together with cyanoacetamide and morpholine to prepare a compound of formula III.

In the above morpholine and the compound R'C(OR) are each preferably employed in a slight excess, for example about up to 20 percent. Also a 5 moderately volatile polar solvent is also desirable to moderate the reaction and to improve the quality of the crystalline product. A lower'alkyl alcohol such as butanol or isopropanol can be used, but acetonitrile is especially preferred for this purpose. An alcohol R OH is formed in the course of the reaction and is consequently always present in the solvent from which the product crystallizes. In the above, the morpholine acts as both a reagent and a catalyst.

A number of other amines, such as aniline, substituted anilines, piperidine, benzylamine, act in a formally similar manner to morpholine, e.g., 3-anilino-2- cyanoacrylamides are known compounds. For the present purpose, however, the stronger bases, such as piperidine and benzylamine, and the anilines suffer from serious disadvantages. For example, the anilines give analytically pure products at all stages but ones which are deeply colored. Removal of these colored contaminants is prohibitively expensive. The disadvantage of the stronger bases, such as piperidine, is that they also catalyze reactions of cyanoacetamideto form pyridine derivatives, which are difficult to remove and are intolerable in the final pharmaceutically active compound. Morpholine (pK c. 8.3), however, has the advantage in that its weak basicity makes it a poor catalyst in the side reactions of cyanoacetamide. Morpholine also has the advantage that it lacks the aromatic reactivity of the anilines and thus colored byproducts, which are probably polymeric, are not formed. Additionally, morpholine has the advantage that the compound of formula (III) has favorable physical properties and can be isolated readily in good yield and in high purity. Thus, the entire reaction requence to a pyrazolo[ 3,4-d]pyrimidine can be carried out without recrystallizations being necessary. In preparing the compound of formula IH the starting materials are preferably mixed together and then heated to reflux, preferably at a temperature above about 60 C to a 45 temperature below about 120 C.

In order to prepare Allopurinol, the compound of formula III, in this case R hydrogen, is reacted with hydrazine to form the compound of formula II where R is hydrogen and thereafter the compound of formula II is reacted with formamide and/or formic acid to fonn Allopurinol. The base of formula II is produced in this reaction, but is isolated as a salt, preferably a salt of a pharmaceutically acceptable acid. The present method 55 is particularly preferred for use in the preparation of Allopurinol since a pure product is provided without necessity of isolating intermediates.

In another aspect, this invention provides a method for preparing novel and useful intermediate pyrazoles 60 or pharmaceutically acceptable salts thereof (useful in preparing useful derivatives of Allopurinol), shown as the compounds of the formula (IV) 4 where R is lower alkyl (methyl, ethyl, propyl, and butyl). These compounds are prepared by reacting hydrazine with a compound of formula III where R is lower alkyl and defined above.

The derivatives of Allopurinol shown in formula V are then prepared by reacting a compound of the formula IV with formic acid and/or formamide as disclosed herein to prepare a compound of formula V.

where R is as defined above. The drugs formed in this invention may be administered with a suitable pharmaceutically acceptable carrier in tablets, capsules-or in other commonly acceptable manner.

The following examples illustrate the invention:

EXAMPLE 1 3-Morpholino-2-cyanoacrylamide A stirred mixture of cyanoacetamide (63 g.), triethylorthoformate (134 g.), morpholine (82.5 g.) and acetonitrile (37.5 ml.) was heated under reflux for 4 hours. The initial reflux temperature was 117 C and the final reflux temperature was 82 C.

At the end of the reflux period the mixture was cooled to 30C and the heavy crystalline precipitate was collected and washed with 2 X ml. of ethanol. The product was dried in vacuo at 30C. Wt. 111 g. Yield 82 percent mp. 173-175C.

EXAMPLE 2 3-Aminopyrazole-4-carboxamide hemi-sulphate To water (253 ml.) at 60 C was added 3- morpholino-Z-cyanoacrylamide (63.4 g.) and 85 percent technical hydrazine hydrate (22.7 g.). The mixture was rapidly heated to C and the temperature was maintained at 90 C for 20 minutes. The mixture was then cooled to 60 C and the pH carefully adjusted to 1.5 by the addition of a mixture of sulphuric acid (45.7 g.) and ice (45.7 g.). The acidified reaction was cooled to 5 C and the crystalline product collected and washed with cold water (2 X ml.) and acetone (2 X 50 ml.). The product was dried in vacuo at 80 C Wt 5.8 g. Yield= 95 percent m.p. 237239 C.

EXAMPLE 3 4-I-Iydroxypyrazolo[3,4-d]pyrimidine A suspension of 3-aminopyrazole-4carboxamide hemisulphate (113 g.) in formamide (325 ml.) was stirred and heated to C. The reaction was held at 145 C for 5 hours. The reaction was then cooled to 30 C and the product collected and washed with formamide (2 X 500 ml.), water (2 X ml.) and acetone (2 X 100 ml.). Wt. of crude product 79 gms. The crude product was recrystallized by dissolution in a solution made from sodium hydroxide (25 g.) in water (1,200 ml.) with treatment at 25 C with charcoal (8 g.), followed by reprecipitation by the addition of concentrated hydrochloric acid to pH 5. The product was collected and washed with cold water (2 X 300 ml.), acetone (2 X 200 ml.) and dried in vacuo at 60 C. Weight 70 g. Yield 80 percent.

3-Methyl-3-morpholino-2-cyanoacrylamide A stirred mixture of cyanoacetamide (84 g.), triethylorthoacetate (178 g.) and morpholine (108 g.) was heated under reflux for 3 hours. The initial reflux temperature was 104 C and the final reflux temperature was 89 C. At the end of the reflux period acetonitrile (50 ml.) was added, the mixture was cooled at 25 C, the crystalline precipitate was collected, and washed with 2 X 100 ml. of cold ethanol. Weight X 104.7 g. Yield 53 percent. A sample was recrystallized from ethanol as white needles mp. 173-l 74.5 C.

EXAMPLE 5 3-Ethyl-3-morpholino-2-cyanoacrylamide A stirred mixture of cyanoacetamide (84 g.), triethylorthopropionate (193 g.) and morpholine (108 g.) was heated under reflux for 3 hours. The initial reflux temperature was 121 C and the final reflux temperature was 91 C. At the end of the reflux period acetonitrile (50 ml.) was added, the mixture was cooled to 25 C, the crystalline precipitate was collected, and washed with 2 X 100 ml. of cold ethanol. Weight 87 g. Yield 42 percent. A sample was recrystallized from ethanol as white needles mp. 158 C.

EXAMPLE 6 3-morpholino-2-cyanoacrylamide (MCA) Place 67.4 Kg. of cyanoacetamide, 143.9 Kg. of triethylorthoformate, 88.2 Kg. of morpholine, and 33.0 Kg. of acetonitrile in a suitable 100 gallon reactor equipped with a stirrer and a reflux condenser.

Heat the batch to reflux and continue refluxing for 4 hours. The initial reflux temperature shouldbe above 100 C. and the final reflux temperature should be approximately 82 C. In large scale operations such as this, it is preferable to seed the batch periodically and more preferably about every 30 minutes with 3- morpholino-Z-cyanoacrylamide after initial reflux until copious precipitation is obvious.

After the reflux period is complete, preferably cool the batch rapidly to 30i1 C and centrifuge. The wash is a blend of a lower alcohol 74.9 Kg., 10.7 liters of water, and 10.7 Kg. of ice. Vacuum dry the MCA at 30 C The reflux temperature thereafter preferably should be less than about 120 C and more than about 60 C.

EXAMPLE 7 3-aminopyrazole-4-carboxamide hemi-sulfate Add 210.5 liters of water to the reactor and heat to C. Add 52.8 Kg. of MCA and readjust the temperature to 70 C. Drain the jacket and add 18.1 Kg. of percent hydrazine hydrate to the reactor. The heat of the reaction will cause the temperature to increase to -100 C over a 5 minute period. 10 minutes after the hydrazine addition cool the reaction to 55-60 C and carefully add a mixture of 37.5 Kg. of sulfuric acid and 37.5 Kg. of ice to pH 1.5 0.2. Cool the batch to preferably 0-5 C and centrifuge. Wash with 66.6 liters of water. The exact quantity of acid required may vary since there is some loss of excess hydrazine and evolved-morpholine during the course of the reaction.

EXAMPLE 8 4-hydroxypyrazolo[3,4-d]pyrimidine Charge 244.8 Kg. of formamide and 71.6 Kg. of 3- aminopyrazole-4-carboxamide 0.1/2 H 80 to a well vented reactor. Heat to -145 C and hold at this temperature for 5 hours. Cool to preferably 5-10 C and centrifuge. Rinse the cake with 50.6 Kg. of formamide followed by 89.2 Kg. of water.

We claim:

1. The method of making 3-amino-4-carboxamidopyrazole which comprises the steps of (a) mixing and heating cyanoacetamide, triethylorthoformate and morpholino-2-cyanoacrylamide with hydrazine.

2. The method of making 3-arnino-4-carboxamidopyrazole hernisulphate which comprises the steps of (a) mixing and heating cyanoacetamide, triethylorthoformate and morpholine to prepare 3- morpholine-Z-cyanoacrylamide, (b) thereafter mixing and heating 3-morpholino-2-cyanoacrylamide with hydrazine and (c) then adding sulphuric acid. 

2. The method of making 3-amino-4-carboxamidopyrazole hemisulphate which comprises the steps of (a) mixing and heating cyanoacetamide, triethylorthoformate and morpholine to prepare 3-morpholine-2-cyanoacrylamide, (b) thereafter mixing and heating 3-morpholino-2-cyanoacrylamide with hydrazine and (c) theN adding sulphuric acid. 